Solid pharmaceutical preparation

ABSTRACT

A solid preparation comprising an insulin sensitizer and an HMG-CoA reductase inhibitor without deteriorating the stabilities of these drugs, wherein said preparation comprises particles containing an insulin sensitizer and particles containing an HMG-CoA reductase inhibitor.

TECHNICAL FIELD

The present invention relates to a solid preparation which comprisesparticles containing-an insulin sensitizer and particles containing anHMG-CoA reductase inhibitor.

BACKGROUND ART

The combination use of an insulin sensitizer and an HMG-CoA reductaseinhibitor is known to be useful for preventing and treatingarteriosclerosis and xanthoma (see EP-A753298) as well as inflammatorydiseases (see EP-A1254667) and others.

DISCLOSURE OF INVENTION

The inventors of the present invention found that the compatibilitybetween an insulin sensitizer and an HMG-CoA reductase inhibitor was notalways good in preparing a solid preparation containing them.

The object of the present invention is to provide a solid preparationcontaining an insulin sensitizer and an HMG-CoA reductase inhibitorwithout deteriorating the stabilities of these drugs.

The inventors of the present invention had devoted themselves to attainthe above-mentioned object and finally found that by using particlescontaining an insulin sensitizer and particles containing an HMG-CoAreductase inhibitor, a solid preparation could be formulated withoutdeteriorating the stabilities of these drugs, resulting in completion ofthe present invention.

Namely, the present invention relates to,

-   (1) a solid preparation comprising particles containing an insulin    sensitizer and particles containing an HMG-CoA reductase inhibitor;-   (2) the solid preparation according to the above (1), wherein the    insulin sensitizer is pioglitazone or a salt thereof;-   (3) the solid preparation according to the above (1), wherein the    insulin sensitizer is rosiglitazone or a salt thereof;-   (4) the solid preparation according to the above (1), wherein the    HMG-CoA reductase inhibitor is atorvastatin or a salt thereof;-   (5) the solid preparation according to the above (1), wherein the    HMG-CoA reductase inhibitor is pravastatin or a salt thereof;-   (6) the solid preparation according to the above (1), wherein the    HMG-CoA reductase inhibitor is simvastatin;-   (7) the solid preparation according to the above (1), wherein the    insulin sensitizer is pioglitazone or a salt thereof and the HMG-CoA    reductase inhibitor is atorvastatin or a salt thereof;-   (8) the solid preparation according to the above (1), wherein the    insulin sensitizer is pioglitazone or a salt thereof and the HMG-CoA    reductase inhibitor is pravastatin or a salt thereof;-   (9) the solid preparation according to the above (1), wherein the    insulin sensitizer is pioglitazone or a salt thereof and the HMG-CoA    reductase inhibitor is simvastatin;-   (10) the solid preparation according the above (1), which is a    multi-layered tablet wherein the particles containing an insulin    sensitizer and the particles containing an HMG-CoA reductase    inhibitor are contained in separate layers; and others.

According to the present invention, a solid preparation containing aninsulin sensitizer and an HMG-CoA reductase inhibitor wherein thestabilities of these drugs are not deteriorated (namely, degradation ofor decrease in the activities of these drugs are prevented) can beobtained.

Further, according to the present invention, a solid preparation havingexcellent dissolution property of an insulin sensitizer and an HMG-CoAreductase inhibitor can be obtained.

Moreover, according to the present invention, by using an insulinsensitizer and an HMG-CoA reductase inhibitor as separate particles, anyinteraction can be avoided between these drugs or between these drugsand additives. Therefore, according to the present invention, variousadverse effects (for example, degradation of or decrease in theactivities of drugs; change in drug dissolution behavior from apreparation (for example; delay in drug dissolution)) which are causedby said interaction can be prevented.

Furthermore, according to the present invention, by using an insulinsensitizer and an HMG-CoA reductase inhibitor as separate particles, thedissolution behaviors of these drugs from a preparation can beindividually controlled.

DETAILED EXPLANATION OF THE INVENTION

An insulin sensitizer used in the present invention means any drug thatrestores the impaired function of an insulin receptor to the originalstate and thereby improves the insulin resistance, and specificallyincludes pioglitazone, rosiglitazone, reglixane (JTT-501), GI-262570,netoglitazone (MCC-555), YM-440, balaglitazone (DRF-2593), MB-13.1258,5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-[4-(trifluoromethyl)benzyl]benzamide(KRP-297), rivoglitazone (CS-011), FK-614, compounds described inWO99/58510 (e.g.(E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyricacid), tesaglitazar (AZ-242), ragaglitazar (NN-622), muraglitazar(BMS-298585), ONO-5816, LM-4156, MBX-102, LY-519818, MX-6054 andLY-510929.

The insulin sensitizer may be in the form of a salt. Such a salt may bea pharmacologically acceptable salt including salts with inorganicbases, salts with organic bases, salts with inorganic acids, salts withorganic acids and salts with basic or acidic amino acids.

Preferred examples of the salts with inorganic bases include salts withalkali metals such as sodium and potassium; alkaline earth metals suchas calcium and magnesium; aluminum, ammonium and the like.

Preferred examples of the salts with organic bases include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine and the like.

Preferred examples of the salts with inorganic acids include salts withhydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid and the like.

Preferred examples of the salts with organic acids include salts withformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acidand the like.

Preferred examples of the salts with basic amino acids include saltswith arginine, lysine, ornithine and the like.

Preferred examples of the salts with acidic amino acids include saltswith aspartic acid, glutamic acid and the like.

The insulin sensitizer may be anhydrous or hydrous and may be alsolabeled with an isotope (for example, ³H, ¹⁴C, ³⁵S, ¹²⁵I) or the like.

The insulin sensitizer used in the present invention may be a mixture oftwo or more kinds at an appropriate proportion.

The insulin sensitizer is preferably pioglitazone or a salt thereof(preferably, hydrochloride) or rosiglitazone or a salt thereof(preferably, maleate) and more preferably pioglitazone hydrochloride.

An HMG-CoA reductase inhibitor used in the present invention means anydrug that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoA reductase), which is an enzyme in rate-determining step ofcholesterol biosynthesis, and specifically includes atorvastatin,pravastatin, cerivastatin, simvastatin, lovastatin, fluvastatin,itavastatin, rosuvastatin and pitavastatin.

The HMG-CoA reductase inhibitor may be in the form of a salt. Such asalt includes salts exemplified above for an insulin sensitizer.

Moreover, the HMG-CoA reductase inhibitor may be anhydrous or hydrousand may be also labeled with an isotope (for example, ³H, ¹⁴C, ³⁵S,¹²⁵I) or the like.

The HMG-CoA reductase inhibitor used in the present invention may be amixture of two or more kinds at an appropriate proportion.

The HMG-CoA reductase inhibitor is preferably atorvastatin or a saltthereof (preferably, calcium salt), pravastatin or a salt thereof(preferably, sodium salt), simvastatin, pitavastatin or a salt thereof(preferably, calcium salt), and more preferably simvastatin.

In the present invention, preferred combinations of an insulinsensitizer and an HMG-CoA reductase inhibitor include,

-   (1) a combination of pioglitazone or a salt thereof (preferably,    hydrochloride) and atorvastatin or a salt thereof (preferably,    calcium salt);-   (2) a combination of pioglitazone or a salt thereof (preferably,    hydrochloride) and pravastatin or a salt thereof (preferably, sodium    salt);-   (3) a combination of pioglitazone or a salt thereof (preferably,    hydrochloride) and simvastatin;-   (4) a combination of pioglitazone or a salt thereof (preferably,    hydrochloride) and pitavastatin or a salt thereof (preferably,    calcium salt);-   (5) a combination of rosiglitazone or a salt thereof (preferably,    maleate) and atorvastatin or a salt thereof (preferably, calcium    salt);-   (6) a combination of rosiglitazone or a salt thereof (preferably,    maleate) and pravastatin or a salt thereof (preferably, sodium    salt);-   (7) a combination of rosiglitazone or a salt thereof (preferably,    maleate) and simvastatin; and-   (8) a combination of rosiglitazone or a salt thereof (preferably,    maleate) and pitavastatin or a salt thereof (preferably, calcium    salt).

A solid preparation of the present invention comprises particlescontaining an insulin sensitizer and particles containing an HMG-CoAreductase inhibitor (hereinafter, these particles may be simply referredto as the particles of the present invention).

The term “particles”, when used herein, means particles with almostuniform shape and size, which can be obtained by granulating materialsin powder, lump, solution or molten liquid form by a wet granulationmethod, a dry granulation method or a heated granulation method.

The particles of the present invention include powders, fine granulesand granules, each of which preferably has particle size distributionprescribed in Japanese Pharmacopoeia 14th Edition.

Namely, according to Japanese Pharmacopoeia 14th Edition, when theparticle size distribution test of preparations is performed, powdersare defined preferably as “all the powders pass through a No. 18 (850am) sieve and not more than 5% of total powders remain on a No. 30 (500μm) sieve”, fine granules are defined preferably as “powders with notmore than 10% of the total passing through a No. 200 (75 μm) sieve”among the above-mentioned powders, and granules are defined preferablyas “all the granules pass through a No. 10 (1700 μm) sieve, not morethan 5% of total granules remain on a No. 12 (1400 μm), and not morethan 15% of total granules pass through a No. 42 (355 μm) sieve”.

The average diameter of the particles of the present invention isusually 44 to 2000 μm and preferably 75 to 1000 μm.

Although the shape and size of the particles of the present inventionmay vary in process (for example, a compression process) of producing asolid preparation of the present invention, such particles that changein shape and size from the given original ones are also included in theparticles of the present invention.

The repose angle of the particles of the present invention is preferably55° or less and more preferably 50° or less, in view of filling intocapsules, filling into pockets for divided powder, fluidity in tabletingand filling into a mortar in tableting.

The solid preparation of the present invention and the particles of thepresent invention may contain additives conventionally used in thepharmaceutical technology field. Such additives include excipients,disintegrants, binders, lubricants, coloring agents, pH adjusters,surfactants, stabilizers, acidulants, flavors, fluidizing agents andsweetenings. A mixture of two or more these additives at an appropriateproportion may be used. The amounts used of additives are determined inaccordance with quantities conventionally used in the pharmaceuticaltechnology field.

Excipients include starches such as corn starch, potato starch, wheatstarch, rice starch, partially pregelatinized (α) starch, pregelatinized(α) starch and porous starch; saccharides or sugar alcohols such aslactose, fructose, glucose, mannitol and sorbitol; anhydrous calciumphosphate, crystalline cellulose, precipitated calcium carbonate, andcalcium silicate.

Disintegrants include carboxymethylcellulose, carboxymethylcellulosecalcium, carboxymethylstarch sodium, croscarmellose sodium,crospovidone, low-substituted hydroxypropylcellulose and hydroxypropylstarch.

Binders include hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone and gum arabic powder.

Lubricants include magnesium stearate, calcium stearate, talc, sucrosefatty acid ester and sodium stearyl fumarate.

Coloring agents include food dyes such as food Yellow No. 5, food RedNo. 2 and food Blue No. 2; food lake pigments and iron sesquioxide. pHadjusters include citrate, phosphate, carbonate, tartrate, fumarate,acetate and amino acid salt.

Surfactants include polysorbate, polyoxyethylene hardened castor oil,polyoxyethylene (160) polyoxypropylene (30) glycol and sodium laurylsulfate.

Stabilizers include sodium ascorbate, tocopherol, edetate tetrasodium,nicotinic acid amide, cyclodextrins; alkaline earth metal salts (forexample, calcium carbonate, calcium hydroxide, magnesium carbonate,magnesium hydroxide, magnesium silicate, and magnesium aluminate),butylhydroxyanisole, ascorbic acid, and citric acid. The solidpreparation and particles of the present invention preferably contain astabilizer. The amount used of said stabilizer is, for example, 0.01 to10 parts by weight, preferably 0.1 to 5 parts by weight per 100 parts byweight of an HMG-CoA reductase inhibitor. In the case where simvastatinis used as an HMG-CoA reductase inhibitor, in particular, it ispreferable that at least one selected from butylhydroxyanisole, ascorbicacid and citric acid is used as a stabilizer.

Acidulants include ascorbic acid, citric acid, tartaric acid and malicacid.

Flavors include menthol, peppermint oil, lemon oil and vanillin.

Fluidizing agents include light anhydrous silicic acid and hydroussilicon dioxide. Light anhydrous silicic acid may contain hydroussilicon dioxide (SiO₂.nH₂O) (wherein n indicates an integer) as the mainconstituent and specifically includes Sylysia 320 (trade name; FujiSilysia Chemical LTD) and AEROSIL 200 (trade name, Nippon Aerosil CO.,LTD).

Sweetenings include Aspartame, Acesulfame K and saccharin sodium.

Additives include dissolution accelerators for active ingredients,namely, acids such as phosphoric acid, malonic acid, succinic acid,DL-malic acid, tartaric acid, maleic acid, fumaric acid and citric acid;and basic compounds such as sodium carbonate, sodium hydrogen carbonate,sodium citrate and sodium tartrate.

The particles of the present invention can be produced by granulating aninsulin sensitizer or an HMG-CoA reductase inhibitor together with, ifnecessary, the above-mentioned additives, according to a conventionalmethod in the pharmaceutical technology field. Granulation may beperformed by wet granulation, dry granulation or heated granulationtechniques and specifically, a high speed stirring granulator, a fluidbed granulator dryer, an extrusion granulator, a roller compactor, orthe like can be used for granulation. After granulation, additionalsteps such as drying and sizing may be performed if necessary.

The content of an insulin sensitizer in the particles of the presentinvention is, for example, 0.01 to 100 parts by weight, preferably 0.1to 90 parts by weight per 100 parts by weight of the particles of thepresent invention.

Specifically, when the insulin sensitizer is pioglitazone or a saltthereof (preferably, hydrochloride), the content of pioglitazone or asalt thereof is preferably 0.01 to 100 parts by weight, more preferably1 to 90 parts by weight per 100 parts by weight of the particles of thepresent invention.

The content of an HMG-CoA reductase inhibitor in the particles of thepresent invention is, for example, 0.01 to 100 parts by weight,preferably 0.1 to 90 parts by weight per 100 parts by weight of theparticles of the present invention.

Specifically, when the HMG-CoA reductase inhibitor is atorvastatin or asalt thereof (preferably calcium salt), pravastatin or a salt thereof(preferably sodium salt), simvastatin, or pitavastatin or a salt thereof(preferably calcium salt), the content of atorvastatin or a saltthereof, pravastatin or a salt thereof, simvastatin, or pitavastatin ora salt thereof is, for example, preferably 0.01 to 100 parts by weight,more preferably 1 to 90 parts by weight per 100 parts by weight of theparticles of the present invention.

The dosage forms of the solid preparation of the present inventioninclude oral preparations such as tablets (including sublingual tabletsand intraorally disintegrating tablets), capsules (including softcapsules and microcapsules), powder, granules and troches; andparenteral preparations such as external preparations (for example,transdermal preparations and ointments), suppositories (for example,rectal suppositories and vaginal suppositories) and pellets. Thesepreparations may be controlled-release preparations such asimmediate-release preparations or sustained-release preparations (forexample, sustained-release microcapsules).

The solid preparation of the present invention may be in round, capletor oblong form.

The solid preparation of the present invention can be produced byformulating the particles of the present invention together with, ifnecessary, the above-mentioned additives according to a conventionalmethod in the pharmaceutical technology field.

The formulation may be performed by combining granulation, mixing,filling into capsules, compression, coating and the like appropriately.The granulation is performed using a granulator such as a stirringgranulator or a fluid bed granulator, the mixing is performed using amixer such as a V-shape mixer or a tumbling mixer, and the compressionis performed using, for example, a single-punch tableting machine or arotary tableting machine and usually under a pressure of 0.3 to 35kN/cm². The coating is performed using, for example, a film coatingmachine and a coating base may. be, for example, a sugar-coating base, awater soluble film coating base, an enteric film coating base orsustained-release film coating base.

The sugar-coating base may be saccharose and one or more speciesselected from talc, precipitated calcium carbonate, gelatin, gum arabic,pullulan and carnauba wax may be used in combination.

The water soluble film coating base includes cellulose polymers such ashydroxypropylcellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose and methylhydroxyethyl cellulose; synthesizedpolymers such as polyvinylacetal diethylaminoacetate,aminoalkylmethacrylate copolymer E [Eudragit E (trade name), RoehmPharma] and polyvinylpyrrolidone; and polysaccharides such as pullulan.

The enteric film coating base includes cellulose polymers such ashydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, carboxymethylethylcellulose and cellulose acetatephthalate; acrylic acid polymers such as methacrylic acid copolymer L[Eudragit L (trade name), Roehm Pharma], methacrylic acid copolymer LD[Eudragit L-30D55 (trade name), Roehm Pharma] and methacrylic acidcopolymer S [Eudragit S (trade name), Roehm Pharma]; and naturalproducts such as shellac.

The sustained-release film coating base includes cellulose polymers suchas ethyl cellulose; and acrylic acid polymers such asaminoalkylmethacrylate copolymer RS [Eudragit RS (trade name), RoehmPharma] and ethyl acrylate/methyl methacrylate copolymer suspension[Eudragit NE (trade name), Roehm Pharma].

Two or more of the above-mentioned coating bases may be mixed at anappropriate proportion and then used. In a coating step, alight-blocking agent and/or a coloring agent such as titanium dioxide,talc, iron sesquioxide and yellow iron sesquioxide; a plasticizer suchas polyethylene glycol, triethyl citrate, castor oil or polysorbates; ororganic acid such as citric acid, tartaric acid, malic acid or ascorbicacid may be also used.

The solid preparation of the present invention may be printed with amark or a letter for discrimination and may have a cleavage line forbeing divided.

Specific examples of the solid preparation of the present inventioninclude,

-   (1) mixed powder obtained by mixing the particles of the present    invention together with, if necessary, the above-mentioned    additives;-   (2) a capsule obtained by mixing the particles of the present    invention together with, if necessary, the above-mentioned additives    and then filling the mixture into a capsule (for example, a gelatin    capsule);-   (3) a molded product (for example, a tablet) obtained by mixing the    particles of the present invention together with, if necessary, the    above-mentioned additives and then compression molding the mixture;-   (4) a molded product (for example, a dry-coated tablet) obtained by    mixing one of the two kinds of particles of the present invention    together with, if necessary, the above-mentioned additives and then    compression molding the mixture to obtain a molded product (for    example, a tablet), and mixing the other kind of particles together    with, if necessary, the above-mentioned additives and then    compressing the mixture around the above-mentioned molded product;-   (5) a molded product (for example, a layered tablet (a multi-layered    tablet)) obtained by mixing one of the two kinds of particles of the    present invention together with, if necessary, the above-mentioned    additives and then compression molding the mixture to obtain a    molded product (for example, a tablet), and mixing the other kind of    particles together with, if necessary, the above-mentioned additives    and then compressing the mixture around the above-mentioned molded    product in layered form; and-   (6) a capsule obtained by filling any one of the molded products    described in the above 3) to 5) (namely, a tablet, a dry-coated    tablet and a layered tablet (a multi-layered tablet)) into a capsule    (for example, a gelatin capsule).

In preparing the molded products described in the above 4) and 5)(namely, a dry-coated tablet and a layered tablet(a multi-layeredtablet)), an intermediate layer of an inert additive (for example, anexcipient) may be provided in order to prevent any direct contactbetween the drugs contained in the particles of the present invention.

Among the above-mentioned various molded products, the molded productsdescribed in the above 4) and 5) (namely, a dry-coated tablet and alayered tablet (a multi-layered tablet)) are preferable.

Namely, the solid preparation of the present invention is preferably amulti-layered tablet wherein particles containing an insulin sensitizerand particles containing an HMG-CoA reductase inhibitor are contained inseparate layers. Said multi-layered tablet is preferably a two-layeredtablet comprising (1) one layer containing particles of an insulinsensitizer and (2) the other layer containing particles of an HMG-CoAreductase inhibitor; or a three-layered tablet wherein an inertintermediate layer lies between these two layers.

As the solid preparation of the present invention, also preferred is thecapsule described in the above 2). The particles of the presentinvention to be filled into said capsule are preferably granules.

The content of the particles of the present invention in the solidpreparation of the present invention is, for example, 0.1 to 100 partsby weight, preferably 1 to 100 parts by weight per 100 parts by weightof the solid preparation of the present invention.

The content of an insulin sensitizer in the solid preparation of thepresent invention is, for example, 0.01 to 99 parts by weight,preferably 0.1 to 80 parts by weight per 100 parts by weight of thesolid preparation of the present invention.

In the case where the insulin sensitizer is pioglitazone or a saltthereof (preferably, hydrochloride), the content of pioglitazone or asalt thereof in the solid preparation of the present invention ispreferably 0.1 to 80 parts by weight, more preferably 1 to 50 parts byweight per 100 parts by weight of the solid preparation of the presentinvention.

The content of an HMG-CoA reductase inhibitor in the solid preparationof the present invention is, for example, 0.01 to 99 parts by weight,preferably 0.1 to 80 parts by weight per 100 parts by weight of thesolid preparation of the present invention.

In the case where the HMG-CoA reductase inhibitor is atrovastatin or asalt thereof (preferably, calcium salt), pravastatin or a salt thereof(preferably, sodium salt), simvastatin, or pitavastatin or a saltthereof (preferably, calcium salt), the content of atrovastatin or asalt thereof, pravastatin or a salt thereof, simvastatin, orpitavastatin or a salt thereof in the solid preparation of the presentinvention is preferably 0.1 to 80 parts by weight, more preferably 1 to50 parts by weight per 100 parts by weight of the solid preparation ofthe present invention.

The solid preparation of the present invention has less toxicity and canbe orally or parenterally administered to mammals (for example, mice,rats, rabbits, cats, dogs, bovines, horses, monkeys, human being, andothers) safely.

The solid preparation of the present invention is useful as a preventingand treating agent for, for example, glycometabolism disorder,lipidmetabolism disorder, diabetes (for example, type 1 diabetes, type 2diabetes, gestational diabetes), hyperlipemia (for example,hypertriglyceridemia, (familial) hypercholesterolemia, hypo-high densitylipoproteinemia, postprandial hyperlipemia), impaired glucose tolerance(IGT), diabetic complications (for example, neuropathy, nephropathy,retinopathy, cataract, macroangiopathy, osteopenia, diabetichyperosmolar coma, infections (for example, respiratory tract infection,urinary tract infection, alimentary canal infection, dermal soft tissueinfection, inferior limb infection), diabetic gangrene, xerostomia,hypacusis, cerebrovascular disorder, peripheral blood circulationdisorder], obesity, osteoporosis, cachexia (for example, cancerouscachexia, tuberculous cachexia, diabetic cachexia, hemopathic cachexia,endocrinopathic cachexia, infectious cachexia, or AIDS-inducedcachexia), fatty liver, hypertension, polycystic ovary syndrome, renaldiseases (for example, diabetic nephropathy, glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,end-stage renal diseases), muscular dystrophy, myocardial infarction,angina pectoris, cerebrovascular disorder (for example, cerebralinfarction, cerebral stroke), insulin resistant syndrome, syndrome X,dysmetabolic syndrome, hyperinsulinemia, hyperinsulinemia-inducedsensory disorder, tumors (for example, leukemia, breast cancer, prostatecancer, skin cancer), irritable bowel syndrome, acute/chronic diarrhea,inflammatory diseases [for example, Alzheimer's disease, chronicrheumatoid arthritis, spondylitis deformans, arthritis deformans,lumbago, gout, postoperative or traumatic inflammation, swelling,neuralgia, pharyngitis, cystitis, hepatitis (including non-alcoholicfatty hepatitis), pneumonia, pancreatitis, inflammatory colonic disease,ulcerative colitis], visceral obesity syndrome, or arteriosclerosis (forexample, atherosclerosis).

The solid preparation of the present invention is also useful forsecondary prevention of the above-mentioned various diseases (forexample, secondary prevention of cardiovascular events such asmyocardial infarction) and inhibition of progression in these diseases(for example, inhibition of the progression from impaired glucosetolerance to diabetes, or inhibition of the progression toarteriosclerosis in diabetic patients).

A dose of the solid preparation of the present invention may be aneffective amount based on an insulin sensitizer and an HMG-CoA reductaseinhibitor contained in said solid preparation.

The effective amount of an insulin sensitizer is usually 0.01 to 500mg/day, preferably 0.1 to 100 mg/day per adult (60 kg body weight).

In the case where the insulin sensitizer is pioglitazone hydrochloride,the effective amount of pioglitazone hydrochloride is usually 7.5 to 60mg/day, preferably 15 to 45 mg/day per adult (60 kg body weight).

In the case where the insulin sensitizer is rosiglitazone maleate, theeffective amount of rosiglitazone maleate is usually 1 to 12 mg/day,preferably 2 to 8 mg/day per adult (60 kg body weight).

The effective amount of an HMG-CoA reductase inhibitor is usually 0.01to 500 mg/day per, preferably 1 to 100 mg/day per adult (60 kg bodyweight).

In the case where the HMG-CoA reductase inhibitor is atorvastatincalcium, the effective amount of atorvastatin calcium is usually 1 to100 mg/day, preferably, 5 to 80 mg/day per adult (60 kg body weight).

In the case where the HMG-CoA reductase inhibitor is pravastatin sodium,the effective amount of pravastatin sodium is usually 1 to 100 mg/day,preferably 5 to 50 mg/day per adult (60 kg body weight).

In the case where the HMG-CoA reductase inhibitor is simvastatin, theeffective amount of sinvastatin is usually 1 to 160 mg/day, preferably 5to 80 mg/day per adult (60 kg body weight).

In the case where the HMG-CoA reductase inhibitor is pitavastatincalcium, the effective amount of pitavastatin calcium is usually 0.5 to10 mg/day, preferably 1 to 4 mg/day per adult (60 kg body weight).

In the solid preparation of the present invention, the combination ratiobetween an insulin sensitizer and an HMG-CoA reductase inhibitor can beselected appropriately depending on a subject to be administered,disease to be treated, a combination of drugs and the like. For example,0.01 to 100 parts by weight, preferably 0.1 to 10 parts by weight of anHMG-CoA reductase inhibitor may be usually used per 1 part by weight ofan insulin sensitizer.

By using the solid preparation of the present invention, superioreffects such as 1) enhanced actions of an insulin sensitizer and/or anHMG-CoA reductase inhibitor (for example, preventing and treating actionof diabetes, hypercholesterolemia and the like), 2) reduced dosages ofan insulin sensitizer and/or an HMG-CoA reductase inhibitor, 3) reducedadverse effects (for example, increase of body weight, rhabdomyolysis,myopathy, liver dysfunction, jaundice, hypersensitivity) of an insulinsensitizer and/or an HMG-CoA reductase inhibitor can be obtained ascompared with single use of an insulin sensitizer or an HMG-CoAreductase inhibitor.

The solid preparation of the present invention may be used incombination with a concomitant drug which has no adverse effects on aninsulin sensitizer or an HMG-CoA reductase inhibitor. Such a concomitantdrug includes one or more selected from “diabetic treating agents(excluding insulin sensitizers)”, “diabetic complication treatingagents”, “anti-obesity drugs”, “hypotensive drugs”, “antithromboticdrugs”, “hyperlipemia treating agents (excluding HMG-CoA reductaseinhibitors)” and “diuretics”.

The “diabetic treating agents (excluding insulin sensitizers)” includeinsulin preparations (for example, animal-derived insulin preparationsextracted from bovine or swine pancreas; human insulin preparationswhich are synthesized with genetic engineering using Escherichia coli oryeast; insulin zinc; protamine insulin zinc; insulin fragments orderivatives (for example, INS-1)), α-glucosidase inhibitors (forexample, voglibose, acarbose, miglitol, emiglitate), biguanide agents[for example, phenformin, metformin, buformin, or their salts (forexample, hydrochloride, fumarate, succinate)], insulin secretagogues[sulfonylurea agents (for example, tolbutamide, glibenclamide,gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide,glimepiride, glipizide, glybuzole), repaglinide, nateglinide,mitiglinide or its calcium salt hydrate, GLP-1], dipeptidylpeptidase IVinhibitors (for example, NVP-DPP-278, PT-100, NVP-DPP-728, LAF237, orthe like), β3 agonists (for example, CL-316243, SR-58611-A, UL-TG-307,S-226552, AJ-9677, BMS-196085, AZ-40140), amylin agonists (for example,pramlintide), phosphotyrosine phosphatase inhibitors (for example,sodium vanadate), glyconeogenesis inhibitors (for example, glycogenphosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagonantagonists), and Sodium-glucose cotransporter (SGLUT) inhibitors (forexample, T-1095).

The “diabetic complication treating agents” include aldose reductaseinhibitors (for example, tolrestat, epalrestat, zenarestat, zopolrestat,minalrestat, fidarestat (SNK-860), CT-112), neurotrophic factors (forexample, NGF, NT-3, BDNF), neurotrophic factor production/secretionpromotors [for example, neurotrophin production/secretion promotorsdescribed in WO01/14372, for example,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-(3-(2-methylphenoxy)propyl)oxazole)],PKC inhibitors (for example, LY-333531), AGE inhibitors (for example,ALT946, pimagedine, piratoxathin, N-phenacylthiazolium bromide (ALT766),EXO-226), active oxygen scavengers (for example, thioctic acid) andcerebral vasodilators (for example, tiapride, mexiletine).

The “anti-obesity drugs” include central anti-obesity drugs (forexample, dexfenfluramine, fenfluramine, phentermine, sibutramine,amphepramone, dexanphetamine, mazindol, phenylpropanolamine,clobenzorex), pancreatic lipase inhibitors (for example, orlistat), β3agonists (for example, CL-316243, SR-58611-A, UL-TG-307, SB-226552,AJ-9677, BMS-196085, AZ-40140), peptidic anorectics (for example,leptin, CNTF (ciliary neurotrophic factors)) and cholecystokininagonists (for example, lintitript, FPL-15849).

The “hypotensive drugs” include angiotensin converting enzyme inhibitors(for example, captopril, enalapril, delapril), angiotensin IIantagonists (for example, candesartan, cilexetil, losartan, eprosartan,valsartan, telmisartan, irbesartan, tasosartan), calcium antagonists(for example, manidipine, nifedipine, nicardipine, amlodipine,efonidipine), potassium channel openers (for example, levcromakalim,L-27152, AL 0671, NIP-121), and clonidine.

The “antithrombotic drugs” include heparin (for example, heparin sodium,heparin calcium, dalteparin sodium), warfarin (for example, warfarinpotassium), anti-thrombin agents (for example, aragatroban),thrombolytic agents (for example, urokinase, tisokinase, alteplase,nateplase, monteplase, pamiteplase), platelet aggregation inhibitors(for example, ticlopidine hydrochloride), cilostazol, ethylicosapentate, beraprost sodium and sarpogrelate hydrochloride.

The “hyperlipemia treating agents (excluding HMG-CoA reductaseinhibitors)” include fibrate compounds (for example, benzafibrate,beclobrate, binifibrate, ciprofibrate, clinofibrate, clofibrate,clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate,pirifibrate, ronifibrate, simfibrate, theofibrate), squalene synthaseinhibitors (for example, the compounds described in WO97/10224, forexample,1-[((3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl]acetyl]piperidine-4-aceticacid), ACAT inhibitors (for example, Avasimibe, Eflucimibe),anion-exchange resins (for example, cholestyramine), probucol andnicotinic acid drugs (for example, nicomol, niceritrol, ethylicosapentate, phytosterol (for example, soysterol), y-oryzanol).

The “diuretics” include xanthine derivatives (for example, sodiumsalicylate theobromine, calcium salicylate theobromine), thiazide agents(for example, ethiazide, cyclopenthiazide, trichlormethiazide,hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide,penflutizide, polythiazide and methyclothiazide), anti-aldosterone drugs(for example, spironolactone, triamterene), carbonic anhydraseinhibitors (for example, acetazolamide), chlorobenzenesulfonamide drugs(for example, chlorthalidone, mefruside, indapamide), azosemide,isosorbide, etacrynic acid, piretanide, bumetanide and furosemide.

The timing of administration of the solid preparation of thepresent.invention and a concomitant drug is not limited and they may beadministered simultaneously or at staggered times. Alternatively, asingle dosage form containing the solid preparation of the presentinvention and a concomitant drug may be administered to a subject.

A dose of a concomitant drug can be selected appropriately based on theclinical dose. The combination ratio between the solid preparation ofthe present invention and a concomitant drug can be selectedappropriately depending on a subject to be administered, anadministration route, disease to be treated, symptoms and a combinationof drugs. In the case where a subject to be administered is a human,0.01 to 100 parts by weight of a concomitant drug may be used per 1 partby weight of the solid preparation.

Thus, by using a concomitant drug, superior effects such as 1) enhancedactions of the solid preparation of the present invention and aconcomitant drug (synergistic action of the drugs), 2) reduced dosagesof the solid preparation of the present invention or a concomitant drug(reduction in dosage compared with those when they are administeredindividually) and 3) reduced adverse effects of the solid preparation ofthe present invention and a concomitant drug can be obtained.

Hereinafter, the present invention will be explained in detail withreference to Reference Examples, Examples and Experimental Exampleswhich are not intended to limit the present invention.

In the following Reference Examples and Examples, products that meet theJapanese Pharmacopoeia 14th Edition were used as various additives suchas magnesium stearate. The symbol % shown in the Reference Examples andExamples indicates % by weight, unless otherwise specified.

REFERENCE EXAMPLE 1 Production of Mixed Powder Containing AtorvastatinCalcium

Atorvastatin calcium (43.4 g) that is previously ground with an atomizergrinding machine (Fuji Paudal CO., LTD, Model K-II-1, screen size 2.0mmø), calcium carbonate (75.2 g) (NITTO FUNKA KOGYO KK), crystallinecellulose (136.6 g) (trade name: PH101, Asahi KASEI Corporation),lactose (54.4 g) (Maigret) and croscarmellose sodium (FMC) (10.2 g) areput in a fluid bed granulator (POWREX Corporation, LAB-1). Thereto asolution of polysorbate 80 (1.36 g) (trade name: RHEODOL TW-0120, KaoCorporation) and hydroxypropylcellulose (6.84 g) (NISSO) in water (116mL) is sprayed and the mixture is granulated and dried to obtaingranules. To the resultant granules (311.6 g) are added croscarmellosesodium (9.73 g) and magnesium stearate (1.63 g) (TAIHEI CHEMICALINDUSTRIAL CO., LTD) to obtain mixed powder.

REFERENCE EXAMPLE 2 Production of Mixed Powder Containing AtorvastatinCalcium

Atorvastatin calcium (43.4 g) that is previously ground with an atomizergrinding machine (Fuji Paudal CO., LTD, Model K-II-1, screen size 2.0mmø) and calcium carbonate (75.2 g), crystalline cellulose (136.6 g),lactose (54.4 g) and croscarmellose sodium (10.2 g) are put in a fluidbed granulator (POWREX Corporation, LAB-1). Thereto a solution ofpolysorbate 80 (1.36 g), sodium ascorbate (0.07 g) andhydroxypropylcellulose (6.84 g) in water (116 mL) is sprayed and themixture is granulated and dried to obtain granules. To the resultantgranules (311.6 g) are added croscarmellose sodium (9.73 g) andmagnesium stearate (1.63 g) to obtain mixed powder.

REFERENCE EXAMPLE 3 Production of Mixed Powder Containing PioglitazoneHydrochloride

Pioglitazone hydrochloride (132.2 g), lactose (305.4 g) and carmellosecalcium (14.4 g) (Gotoku Chemical Company LTD.) are put in a fluid bedgranulator (PAUREX Corporation, LAB-1). Thereto a solution ofhydroxypropylcellulose (12.0 g) in water (188 mL) is sprayed and themixture is granulated and dried to obtain granules. To the resultantgranules (440.8 g) are added carmellose calcium (13.7 g) and magnesiumstearate (1.52 g) to obtain mixed powder.

REFERENCE EXAMPLE 4 Production of Mixed Powder Containing Simvastatin

Simvastatin (50.1 g) containing 0.3% of butylhydroxyanisole, lactose(296.25 g), crystalline cellulose (100 g) and citric acid (6.25 g) wereput in a fluid bed granulator (PAUREX COPORATION LAB-1). Thereto asolution of hydroxypropylcellulose (15 g) in water (250 mL) was sprayedand the mixture was granulated and dried to obtain 450 g of granules.The above described process was repeated to obtain another 453 g ofgranules. To the resultant granules (903 g) were added crospovidone(48.24 g) (ISP) and magnesium stearate (14.48 g) to obtain mixed powder.

REFERENCE EXAMPLE 5 Production of Mixed Powder Containing Simvastatin

Simvastatin (60.12 g) containing 0.3% of butylhydroxyanisole, lactose(409.5 g), pregelatinized starch (30 g) (NIPPON STARCH CHEMICALCO.,LTD.) and citric acid (7.5 g) were put in a fluid bed granulator(PAUREX COPORATION, LAB-1). Thereto a dispersion prepared by dispersingpregelatinized starch (30 g) in 33% (v/v) ethanol (125 mL) and thenadding water (375 mL) was sprayed and the mixture was granulated anddried to obtain 518 g of granules. The above described process wasrepeated to obtain another 528 g of granules. To the resultant granules(1046 g) were added crystalline cellulose (58.42 g), crospovidone (46.74g) and magnesium stearate (17.53 g) to obtain mixed powder.

REFERENCE EXAMPLE 6 Production of Mixed Powder Containing PioglitazoneHydrochloride

Pioglitazone hydrochloride (20.5 kg), lactose (44.31 kg) andcroscarmellose calcium (4.464 kg) were put in a fluid bed granulator(PAUREX COPORATION, FD-WSG-60). Thereto 2.232 kg of polyvinylpyrrolidoneK30 (BASF) was sprayed using a solution of polyvinylpyrrolidone K30(3.732 kg) in water (33.59 L), and the mixture was granulated and driedto obtain granules. To the resultant granules (1000 g) were addedcroscarmellose sodium (36.42 g) and magnesium stearate (4.16 g) toobtain mixed powder.

EXAMPLE 1 Production of a Capsule

The mixed powder of Reference Example 1 (85 g) and the mixed powder ofReference Example 3 (120 g) are mixed in a plastic bag. The resultantmixture (205 mg) is filled into a No. 0 gelatin capsule to obtain acapsule containing 10 mg of atorvastatin and 30 mg of pioglitazone.

EXAMPLE 2 Production of a Capsule

Into a No. 0 gelatin capsule, the mixed powder of Reference Example 1(85 mg) and then the mixed powder of Reference Example 3 (120 mg) arefilled to obtain a capsule containing 10 mg of atorvastatin and 30 mg ofpioglitazone.

EXAMPLE 3 Production of Divided Powder

The mixed powder of Reference Example 1 (85 g) and the mixed powder ofReference Example 3 (120 g) are mixed in a plastic bag. The resultantmixture is filled into laminated polyethylene bags in an amount of 205mg per a bag to obtain divided powder containing 10 mg of atorvastatinand 30 mg of pioglitazone per a bag.

EXAMPLE 4 Production of a Layered Tablet

The mixed powder of Reference Example 1 (85 mg) is compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine forLayered Tablets) under a pressure of 0.5 kN/cm² and further, the mixedpowder of Reference Example 3 (120 mg) is compressed under a pressure of5 kN/cm² to obtain a layered tablet. The resultant tablets (205 g) areput in a coating machine (Freund, HCT-20) and coated with a filmsuspension of hydroxypropylmethylcellulose (62.2 g) (trade name: TC-5,Shin-Etsu Chemical Co., LTD), titanium dioxide (12.5 g) (Ishihara SangyoCo., LTD.), polyethylene glycol 6000 (8.32 g) (Sanyo Kasei CO., LTD.),yellow iron sesquioxide (0.12 g) (Ansted) and water (960 g) so as toattain 6 mg of coating per a tablet. Thus a film coated tabletcontaining 10 mg of atorvastatin and 30 mg of pioglitazone is obtained.

EXAMPLE 5 Production of a Layered Tablet

The mixed powder of Reference Example 2 (170 mg) is compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine forLayered Tablets) under a pressure of 0.5 kN/cm² and further, the mixedpowder of Reference Example 3 (120 mg) is compressed under a pressure of5 kN/cm² to obtain a layered tablet. The resultant tablets (205 g) areput in a coating machine (Freund, HCT-20) and coated with a filmsuspension of hydroxypropylmethylcellulose (62.2 g), titanium dioxide(12.5 g), polyethylene glycol 6000 (8.32 g), yellow iron sesquioxide(0.12 g) and water (960 g) so as to attain 9 mg of coating per a tablet.Thus a film coated tablet containing 20 mg of atorvastatin and 30 mg ofpioglitazone is obtained.

EXAMPLE 6 Production of a Dry-Coated Tablet

The mixed powder of Reference Example 1 (85 mg) is compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine for Drycoated Tablets) under a pressure of 5 kN/cm² to obtain a tablet. Theresultant tablet as a core and the mixed powder of Reference Example 3(180 mg) as an outer layer are compressed into a tablet. Thus adry-coated tablet containing 10 mg of atorvastatin and 45 mg ofpioglitazone is obtained.

EXAMPLE 7 Production of a Capsule

Into a No. 0 gelatin capsule, the mixed powder of Reference Example 5(200 mg) and then the mixed powder of Reference Example 6 (120 mg) werefilled to obtain a capsule containing 20 mg of simvastatin and 30 mg ofpioglitazone.

EXAMPLE 8 Production of a Layered Tablet

The mixed powder of Reference Example 4 (400 mg) was compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine forLayered Tablets) under a pressure of 0.5 kN/cm² and further, the mixedpowder of Reference Example 6 (180 mg) was compressed under a pressureof 12 kN/cm² to obtain a layered tablet containing 40 mg of simvastatinand 45 mg of pioglitazone.

EXAMPLE 9 Production of a Layered Tablet

The mixed powder of Reference Example 5 (400 mg) was compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine forLayered Tablets) under a pressure of 0.5 kN/cm² and further, the mixedpowder of Reference Example 6 (180 mg) was compressed under a pressureof 13 kN/cm2 to obtain a layered tablet containing 40 mg of simvastatinand 45 mg of pioglitazone.

EXAMPLE 10 Production of a Film Coated Tablet

The layered tablets (140 g) obtained in Example 9 was put in a coatingmachine (Freund, HCT-20) and coated with a film suspension ofhydroxypropylmethylcellulose (149.2 g), titanium dioxide (20 g),polyethylene glycol 6000 (30 g), iron sesquioxide (0.8 g) and water(2000 g) so as to attain 17.4 mg of coating per a tablet. Thus a filmcoated tablet containing 40 mg of simvastatin and 45 mg of pioglitazonewas obtained.

EXAMPLE 11

The mixed powder of Reference Example 4 (200 mg) is compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine forLayered Tablets) under a pressure of 0.5 kN/cm² and further, the mixedpowder of Reference Example 6 (120 mg) is compressed under a pressure of12 kN/cm² to obtain a layered tablet containing 20 mg of simvastatin and30 mg of pioglitazone.

EXAMPLE 12

The mixed powder of Reference Example 4 (400 mg) is compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine forLayered Tablets) under a pressure of 0.5 kN/cm² and further, the mixedpowder of Reference Example 6 (120 mg) is compressed under a pressure of12 kN/cm² to obtain a layered tablet containing 40 mg of simvastatin and30 mg of pioglitazone.

EXAMPLE 13

The mixed powder of Reference Example 5 (200 mg) is compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine forLayered Tablets) under a pressure of 0.5 kN/cm² and further, the mixedpowder of Reference Example 6 (120 mg) is compressed under a pressure of13 kN/cm² to obtain a layered tablet containing 20 mg of simvastatin and30 mg of pioglitazone.

EXAMPLE 14

The mixed powder of Reference Example 5 (400 mg) is compressed using atableting machine (Kikusui Seisakusho LTD., Tableting Machine forLayered Tablets) under a pressure of 0.5 kN/cm² and further, the mixedpowder of Reference Example 6 (120 mg) is compressed under a pressure of13 kN/cm² to obtain a layered tablet containing 40 mg of simvastatin and30 mg of pioglitazone.

EXPERIMENTAL EXAMPLE

The dissolution of simvastatin and pioglitazone from the layered tabletobtained in Example 9 was tested by a paddle method (50 rev). Ten mMphosphate buffer (37° C., pH 7.0) containing 0.5% sodium dodecyl sulfateand 0.3M potassium chloride-hydrochloric acid buffer (37° C., pH 2.0)were used as dissolution media for Simvastatin and for Pioglitazone,respectively. The result is shown in Table 1. TABLE 1 Dissolution rateof Drug (%) Dissolution rate (%) 10 min. 20 min. 30 min. PreparationDrug after after after Example 9 Simvastatin 98 98 99 Pioglitazone 85 9396

As shown in Table 1, the solid preparation of the present invention hasgood dissolution property of an insulin sensitizer (pioglitazone) and anHMG-CoA reductase inhibitor (simvastatin).

INDUSTRIAL APPLICABILITY

According to the present invention, a solid preparation containing aninsulin sensitizer and an HMG-CoA reductase inhibitor, wherein thestabilities of these drugs are not deteriorated can be obtained.

In addition, according to the present invention, a solid preparationhaving excellent dissolution property of an insulin sensitizer and anHMG-CoA reductase inhibitor can be obtained.

1. A solid preparation comprising particles containing an insulinsensitizer and particles containing an HMG-CoA reductase inhibitor. 2.The solid preparation according to claim 1, wherein the insulinsensitizer is pioglitazone or a salt thereof.
 3. The solid preparationaccording to claim 1, wherein the insulin sensitizer is rosiglitazone ora salt thereof.
 4. The solid preparation according to claim 1, whereinthe HMG-CoA reductase inhibitor is atorvastatin or a salt thereof. 5.The solid preparation according to claim 1, wherein the HMG-CoAreductase inhibitor is pravastatin or a salt thereof.
 6. The solidpreparation according to claim 1, wherein the HMG-CoA reductaseinhibitor is simvastatin.
 7. The solid preparation according to claim 1,wherein the insulin sensitizer is pioglitazone or a salt thereof and theHMG-CoA reductase inhibitor is atorvastatin or a salt thereof.
 8. Thesolid preparation according to claim 1, wherein the insulin sensitizeris pioglitazone or a salt thereof and the HMG-CoA reductase inhibitor ispravastatin or a salt thereof.
 9. The solid preparation according toclaim 1, wherein the insulin sensitizer is pioglitazone or a saltthereof and the HMG-CoA reductase inhibitor is simvastatin.
 10. Thesolid preparation according to claim 1, which is a multi-layered tabletwherein the particles containing an insulin sensitizer and the particlescontaining an HMG-CoA reductase inhibitor are contained in separatelayers.